JPS59130889A - Novel cephalosporin intermediate - Google Patents
Novel cephalosporin intermediateInfo
- Publication number
- JPS59130889A JPS59130889A JP58252263A JP25226383A JPS59130889A JP S59130889 A JPS59130889 A JP S59130889A JP 58252263 A JP58252263 A JP 58252263A JP 25226383 A JP25226383 A JP 25226383A JP S59130889 A JPS59130889 A JP S59130889A
- Authority
- JP
- Japan
- Prior art keywords
- dimethylacetamide
- formula
- acid
- solvate
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
- C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
(57)【要約】本公報は電子出願前の出願データであるた
め要約のデータは記録されません。(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】
本発明は、セフタジジム（ｃｅｆｔａｚｉｄｉｍｅ）の
新規製造法および製造中間体に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method and intermediate for the production of ceftazidime.
各々の抗生物質に特有の病原性微生物耐性株が出現する
恐れが常にあるため、新規な抗生物質の開発が不断に望
まれている。特にセファロスポリン系抗生物質の分野に
おいては、開発製造費が嵩むので、研究者は上記抗生物
質を製造するための新規で有効な方法を常に模索してい
る。Since there is always a risk that pathogenic microorganism-resistant strains specific to each antibiotic will emerge, there is a constant desire to develop new antibiotics. Particularly in the field of cephalosporin antibiotics, development and manufacturing costs are high, so researchers are constantly searching for new and effective methods to produce these antibiotics.
これに関連して、アメリカ合衆国特許＆乞２ 夕１ｉθ
ｔ／には、現在セフタジジムと総称されているセファロ
スポリン系抗生物質である（乙Ｒ，７Ｒ，）−７−［Ｃ
Ｚ）−ノー（２−アミノチアツルーグーイル）−２−（
−２−カルボキシプロプ−２−オキシイミノ）アセトア
ミド］ −３−（／−ピリジニウムメチル）−３−セフ
ェム−ｔ＝カルボン酸エステルの合成が記載されている
。そこに記載されているセフタジジムの合成法は、 （
Ｚ）７２− （２−モーブトキシカルボニルプロプーコ
−オキシイミノ）−２−（２−１−リフェニルメチルア
ミノチアゾルーグーイル）アセチルクロライドと（６Ｒ
１７Ｒ）−７−アミノ−３−（／−ピリジニウムメチル
）−３−セフェム−グーカルボン酸をＮ、ＮＬ−ジメチ
ルアセトアミドおよびアセトニトリル中で反応させてセ
フタジジムの製造中間体、（乙Ｒ１７Ｒ）−７−［（Ｚ
）−ノー（２−トリフェニルメチルアミノチアゾ＼ルー
グーイル） −’２−（２−ｔ−ブトキシカルボニルプ
ロプ−２−オキシイミノ）アセトアミド］−３−（／−
ピリジニウムメチル）−３−セフェム−を−カルボン酸
ニスデルを得′ることがら成る。このセフタジジムの製
造中間体を無定形固体として反応液から回収し２次いで
Ｎ、Ｎ−ジメチルホルムアミドからＮ、Ｎ−ジメチルホ
ルムアミド溶媒和物（中間体１モル当りＤ■゛２ｊモル
）として結晶化させることにより精製した。得られたセ
フタシジムの製造中間体を保護基を除去するためにギ酸
と反応させてセフタジシムを得た。In this connection, United States Patent &
t/ contains (R,7R,)-7-[C
Z)-no(2-aminothiatruguyl)-2-(
-2-carboxyprop-2-oximino)acetamide] The synthesis of -3-(/-pyridiniummethyl)-3-cephem-t=carboxylic acid ester is described. The synthesis method of ceftazidime described therein is (
Z) 72-(2-mobutoxycarbonylpropco-oximino)-2-(2-1-liphenylmethylaminothiazol-guyl)acetyl chloride and (6R
17R)-7-Amino-3-(/-pyridiniummethyl)-3-cephem-gucarboxylic acid is reacted in N,NL-dimethylacetamide and acetonitrile to produce ceftazidime production intermediate, (OtsuR17R)-7-[ (Z
)-no(2-triphenylmethylaminothiazo\rougoyl)-'2-(2-t-butoxycarbonylprop-2-oximino)acetamide]-3-(/-
The process consists of obtaining Nisder (pyridinium methyl)-3-cephem-carboxylic acid. This ceftazidime production intermediate is recovered from the reaction solution as an amorphous solid, and then crystallized from N,N-dimethylformamide as an N,N-dimethylformamide solvate (D 2 j mol per mol of intermediate). It was purified by The obtained ceftasidime production intermediate was reacted with formic acid to remove the protecting group to obtain ceftazime.
本発明はセフタジジムの製造中間体の改良製造法を提供
するものであり８本方法においては、当−該中間体はＮ
、Ｎ−ジメチルアセトアミド溶媒和物として反応液から
直接結晶化する。従って１本発明によれば、続いて精製
を要せず、収率を上げ。The present invention provides an improved method for producing an intermediate for the production of ceftazidime, and in this method, the intermediate is N
, N-dimethylacetamide solvate directly crystallized from the reaction solution. Therefore, according to the present invention, subsequent purification is not required and the yield is increased.
セフタジジムの製造原価を低減させる。Reduce the manufacturing cost of ceftazidime.
本発明に従えば１式（１）
［式中、ＤＭＡＣはＮ、Ｎ−ジメチルアセトアミドを表
わし、Ｘは０３〜３．θである。］
で表わされる化合物は、セフクシシムの有用な合成中間
体である。According to the present invention, formula 1 (1) [wherein, DMAC represents N,N-dimethylacetamide, and X represents 03-3. θ. ] The compound represented by is a useful synthetic intermediate of cefuxisime.
また、 Ｎ、Ｎ−ジメチルアセトアミド中で（Ｚ）−２
−（２−ｔ−プトキシカルボニルプロプーユーオキシイ
ミノ）−２−（，２−トリフェニルメチルアミノチアゾ
ルーｔ−イル）アセチルハライドを（乙Ｒ，７Ｒ）−７
−アミノ−３−（／−ピリジニウムメチル）−３−セフ
ェム−グーカルボン酸塩と反応させることを特徴とする
前記式（１）で表わされる化合物の製造方法をも提供す
る。得られるジメチルアセトアミド溶媒和物は結晶性固
体として反応液から直接単離できる。本発明方法を用い
れば、実質的に純粋なセフクシシムの製造中間体のＮ、
Ｎ−ジメチルアセトアミド溶媒和物を収率良く単離でき
る。Also, (Z)-2 in N,N-dimethylacetamide
-(2-t-ptoxycarbonyl propoxyimino)-2-(,2-triphenylmethylaminothiazol-t-yl)acetyl halide (R, 7R) -7
-Amino-3-(/-pyridiniummethyl)-3-cephem-gucarboxylic acid salt A method for producing the compound represented by formula (1) is also provided. The resulting dimethylacetamide solvate can be isolated directly from the reaction solution as a crystalline solid. Using the method of the present invention, substantially pure cefuxisim production intermediate N,
N-dimethylacetamide solvate can be isolated with good yield.
本明細書の記載全般に亘って用いる′セフクシシムの製
造中間体′とは、（乙Ｒ，７Ｒ）−７−［（Ｚ）−２−
（２−トリフェニルメチルアミノチアツルー弘−イル＞
−ｘ−（，２−ｔ−ブトキシカルホニルプロプーノーオ
キシイミノ）アセトアミド］−３−（／−ピリジニウム
メチル〕−３−セフェム−弘−カルホン酸エステルを意
味する。このセフクシシムの製造中間体を製造する方法
は。The 'production intermediate of cefoxisim' used throughout the description of this specification is (R,7R)-7-[(Z)-2-
(2-triphenylmethylaminothiatruhiroyl>
-x-(,2-t-butoxycarbonylpropinooxyimino)acetamide]-3-(/-pyridiniummethyl]-3-cephem-hiro-carphonic acid ester. This intermediate for the production of cefuxisim. How to manufacture.
セファロスポリン骨格化合物（即ち、７−アミノ−３−
セフェム誘導体）を酸ハライド（普通は酸塩化物）と反
応させることから成る普通のアシル化反応を包含する。Cephalosporin backbone compounds (i.e., 7-amino-3-
common acylation reactions consisting of reacting a cephem derivative) with an acid halide (usually an acid chloride).
上記セフクシシムの製造中間体の合成に使用する典型的
な酸ハライドは、（２）−２−（２−Ｌ−ブトキシカル
ボニルプロプ−λ−オキシイミノ）−２−（２−トリフ
ェニルメチルアミノチアゾルーグーイル）酢酸ハライド
である。上記アシル化反応は、一般的に、酸ハライドと
約等モル量の７−アミノ−３−セフェム骨格化合物を、
ジクロロメタン、アセトンまたはＮ、Ｎ−ジメチルアセ
トアミドとアセトニトリルの混合物などの不活性溶媒中
、トリエチルアミンまたはピリジンなどの塩基の存在下
に反応させることにより実施する。本発明方法は１反応
溶媒としてＮ、Ｎ−ジメチルアセトアミドを使用するこ
とによりセフクシシムの製造中間体を結晶性のＮ、Ｎ−
ジメチルアセトアミド溶媒和物としてアシル化反応液が
ら直接得ることができるという点において改良されてい
る。本改良方法は、セフクシシムの製造中間体をＮ、Ｎ
−ジメチルホルムアミド溶媒和物などの溶媒和物に変換
する分離精製工程を要しない。A typical acid halide used in the synthesis of the intermediate for producing cefoxisim is (2)-2-(2-L-butoxycarbonylprop-λ-oximino)-2-(2-triphenylmethylaminothiazole). Gooyl) is acetic acid halide. The above acylation reaction generally involves using about an equimolar amount of a 7-amino-3-cephem skeleton compound as an acid halide,
The reaction is carried out in an inert solvent such as dichloromethane, acetone or a mixture of N,N-dimethylacetamide and acetonitrile in the presence of a base such as triethylamine or pyridine. The method of the present invention uses N,N-dimethylacetamide as a reaction solvent to convert the production intermediate of cefuxisime into crystalline N,N-
It is improved in that it can be obtained directly from the acylation reaction solution as a dimethylacetamide solvate. In this improved method, the production intermediate of cefuxisim is
- No separation and purification step for converting into a solvate such as dimethylformamide solvate is required.
本発明方法を実施するに当り、酸ハライド、例えば、（
Ｚ）−２−（２−ｔ−ブトキシカルボニルプロプ−２−
オキシイミノ） −２−（２−トリフェニルメチルアミ
ノチアゾルー弘−イル）−アセチルクロライドは、遊離
酸を五塩化リンなどのハロケン化剤と、ジクロロメタン
またはジエチルエーテルなどの適当な溶媒中で反応させ
て製造し得る。酸ハライドが生成したら、普通は単離せ
ずにＮ、Ｎ−ジメチルアセトアミド中で約等モル量のセ
ファロスポリン骨格化合物の懸濁液に加える。この反応
液にトリエチルアミンなどの適当な塩基を加えると存在
し得る全ての遊離酸の除去剤として作用する。上記のア
シル化反応は、約−２θ〜約ｔＯ°Ｃで実施した場合、
普通は約７５〜９０分以内に完了する。こうして製造さ
れるセフクシシムの製造中間体は１式（１）で表わされ
るＮ、Ｎ−ジメチルアセトアミド溶媒和物である。In carrying out the method of the invention, acid halides, such as (
Z)-2-(2-t-butoxycarbonylprop-2-
oximino)-2-(2-triphenylmethylaminothiazol-hiro-yl)-acetyl chloride is prepared by reacting the free acid with a halogenating agent such as phosphorus pentachloride in a suitable solvent such as dichloromethane or diethyl ether. It can be manufactured by Once the acid halide is formed, it is usually not isolated but added to a suspension of about equimolar amounts of the cephalosporin backbone compound in N,N-dimethylacetamide. Addition of a suitable base such as triethylamine to the reaction solution acts as a scavenger for any free acid that may be present. The above acylation reaction, when carried out at about -2θ to about tO°C,
Usually complete within about 75-90 minutes. The production intermediate of cefoxisim thus produced is an N,N-dimethylacetamide solvate represented by formula (1).
（以下余白）
［式中、ＤＭＡＣはＮ、Ｎ−ジメチルアセトアミドを表
わす。Ｘは０５〜３．０であり、セフクシジムの製造中
間体１モル当りのＤＭＡ０のモル数を表わす。］好まし
い溶媒和物はＸが約０３〜約１５．特にＸがＩＯの場合
である。(The following is a margin) [In the formula, DMAC represents N,N-dimethylacetamide. X is 05 to 3.0 and represents the number of moles of DMA0 per mole of the cefuccidime production intermediate. ] Preferred solvates are those in which X is about 03 to about 15. This is especially the case when X is IO.
上記のセフクシジムの製造中間体の溶媒和物は。The above solvate of the production intermediate of cefuccidime is.
所望ならば１反応液を水洗したのち適当な反溶媒。If desired, wash one reaction solution with water and then add a suitable anti-solvent.
即ち、中間体が実質的に不溶である溶媒を加えることに
より容易に単離できる。代表的な反溶媒としては、エー
テル類（ジエチルエーテル、メチルエチルエーテル、ジ
グライムまたはテトラヒドロフランなど）およびエステ
ル類（酢酸エチルまたは酢酸メチルヶと）が例示される
。好ましい反溶媒はジエチルエーテルまたはジエチルエ
ーテルと酢酸エチルを組合せたものである。That is, it can be easily isolated by adding a solvent in which the intermediate is substantially insoluble. Typical antisolvents include ethers (such as diethyl ether, methyl ethyl ether, diglyme, or tetrahydrofuran) and esters (such as ethyl acetate or methyl acetate). A preferred antisolvent is diethyl ether or a combination of diethyl ether and ethyl acetate.
反溶媒をＮ、Ｎ−ツメチルアセ１−アミド反応液に加え
ると、セフクシジムの製造中間体のＮ、Ｎ〜ツメチルア
セトアミド溶媒和物は、溶液を約〜７０〜約十７０℃で
攪拌した場合、約３θ〜約９０分以内に沈澱し始める。When the anti-solvent is added to the N,N-trimethylacetamide reaction solution, the N,N-trimethylacetamide solvate of cefuccidime manufacturing intermediate is dissolved when the solution is stirred at about 70 to about 170°C. Precipitation begins within about 3θ to about 90 minutes.
この結晶性の溶媒和物は単に混液を泊過するたけで単離
されるが、普通、溶媒和物を新しいＮ、Ｎ−ジメチルア
セドア２ドまたハノエチＪｌ／ エーテルで洗浄するの
か望ましい。得られた生成物は室温で風乾するが真空乾
燥して過剰の溶媒を除去できる。製造された生成物は１
通常約９０％以上の純度を有する。セフクシジムの製造
中間体のＮ、Ｎ−ジメチルア士ドアミド溶媒和物である
。The crystalline solvate can be isolated by simply filtering the mixture, but it is usually desirable to wash the solvate with fresh N,N-dimethyl acedo2de or Hanoethyl ether. The resulting product is air dried at room temperature, but can be vacuum dried to remove excess solvent. The product produced is 1
It usually has a purity of about 90% or more. This is an N,N-dimethylamide solvate which is an intermediate for the production of cefuccidime.
本発明で提供するセフクシジムの製造゛中間体の溶媒和
物を直接使用してセフクシジムを製造し得る。例えば、
結晶性の溶媒和物を９ｇ％ギ酸などの酸性溶液に溶解し
てチアゾリルアセトアミド側鎖に付加しｔこアミノ基上
のトリフェニルメチル保護基を開裂し、且つ、同側鎖の
オキシム部分のＬ−ブトキシ保護基を開裂することがで
きる。所望ならば、塩酸を加えてセフクシジムの二塩酸
塩を形成させ、そのことによって結晶性沈澱として最終
産物め単離を促進し得る。製造されたセフクシジム・二
塩酸塩は、抗生物質として使用し得る。The solvate of the intermediate for producing cefuccidime provided by the present invention can be used directly to produce cefuccidime. for example,
The crystalline solvate is dissolved in an acidic solution such as 9 g% formic acid and added to the thiazolyl acetamide side chain to cleave the triphenylmethyl protecting group on the amino group and remove the oxime moiety of the same side chain. The L-butoxy protecting group of can be cleaved. If desired, hydrochloric acid may be added to form the dihydrochloride salt of cefuccidime, thereby facilitating isolation of the final product as a crystalline precipitate. The produced cefuccidime dihydrochloride can be used as an antibiotic.
本発明を更に例示するために、以下に実施例を提示する
が１本発明を制限するものではない。Examples are presented below to further illustrate, but not limit, the invention.
実施例／
（乙Ｒ、７Ｒ）−７−Ｅ（Ｚ）−ノー（２−トリフェニ
ルメチルアミノチアゾルーグーイル）−λ（，２−ｔ
−フトキシヵルポニルプロブー２−オキシイミノ）アセ
トアミド］−３−（／−ピリジニウムメチル）−３−セ
フェムニブ−カルボン酸ニス チル
五塩化リンｆ７０１ （’ｌ／、ｇｍＭ）のジクロロメ
タン／ ３０ ｔｔｔｌ冷攪拌溶液（−７０”Ｃ）に、
（Ｚ）２− （２−ｔ−ブトキシヵルボニルプロブーノ
ーオキシイミノ〕−λ〜（２〜トリフエニルメチルアミ
ノチアシル〜グーイル）０酸２／７２９（３とｍＭ）を
一度に加えた。これを−１０°ｃで３０分間ｍ拌し、ト
リエチルアミン／／乙乙ｍｌ （♂３． ｌ、 ｍ Ｍ
）を含有する水／θθｙｔｔｌの***液で希釈した。Example/ (OtsuR, 7R)-7-E(Z)-no(2-triphenylmethylaminothiazoleguyl)-λ(,2-t
-phthoxycarponylprobu-2-oximino)acetamide]-3-(/-pyridiniummethyl)-3-cefemnib-carboxylic acid phosphorus pentachloride f701 ('l/, gmM) in dichloromethane/30 tttl cold stirring solution (-70"C),
(Z) 2-(2-t-Butoxycarbonylprobunooxyimino)-λ~(2-triphenylmethylaminothiacyl~guyl)0 acid 2/729 (3 mM) was added in one portion. This was stirred at -10°C for 30 minutes, and triethylamine//ml (♂3.l, mM
) with a cold solution of water/θθyttl.
この二相性反応液を約３分間激しく攪拌して有機層を分
取し、（乙Ｒ、７Ｒ）−７−アミノ−３−（／−ピリン
ニウムメチル）−３−セフェム−グーカルボン酸・二塩
酸塩／乙♂９！（３ＫＯｍＭ）を園ｘ チ＃ ７ ｉ
ン２ 乙、 ３ ｙｎｌ （／ ９０ｍＭ）を含有する
Ｎ、Ｎ−ジノチルアセトアミド７９３ｄに懸副した冷攪
拌懸澗液（−７０″Ｃ）に加えた。これをθ〜−Ｊ’Ｃ
で３θ分間攪拌したのち水３００ｙｎｅを一度に加えて
希釈した。この水性反応液を７０分間攪拌して有機層を
分取し、新しいＮ、Ｎ−ジメチルアセトアミド／ｊＯｍ
ｌおまびジエチルエーテル３００ ｙｔｔｌを加えて更
に希釈した。This biphasic reaction solution was vigorously stirred for about 3 minutes, the organic layer was separated, and (R, 7R)-7-amino-3-(/-pyrinnium methyl)-3-cephem-gucarboxylic acid dihydrochloric acid Salt/Otsu♂9! (3KOmM) x Chi # 7 i
It was added to a cold stirred suspension (-70''C) suspended in N,N-dinothylacetamide 793d containing 3ynl (/90mM).
After stirring for 3θ minutes, 300 yne of water was added at once to dilute. The aqueous reaction solution was stirred for 70 minutes, the organic layer was separated, and fresh N,N-dimethylacetamide/jOm
The mixture was further diluted by adding 300 yttl of diethyl ether.
得られた有機溶液を。〜ｊ″Ｃで７時間攪拌し、生成し
た結晶性沈澱を瀘取して、新しいＮ、Ｎ−ジノチルアセ
トアミド、次いで新しいシェチルエーテで洗浄し、常温
で／乙時間真空乾燥して（乙Ｒ２７Ｒ） −７−［（Ｚ
）−２−（，２−ｌ−’Ｊ７エ＝ルメチルアミノチアノ
ルーグーイル）−２−（２−Ｌ−ブトキシカルホニルプ
ロプーノーオキシイミノ）アセドア２１〜］−３−（／
−ピリジニウムメチル）−３−セフェム−グーカルホン
酸エステルのＮ、Ｎ−ジメチルアセトアミド溶媒和物＼
Ｘ＼＼＼＼Ｘ沃火×＼案×Ｎ＼＼＼和−（Ｎ、Ｎ−ジメ
チルアセトアミド１モル）２θ９．＜ｙ（収率乙ｊ２％
）を得た。’Ｐ、／３０°Ｃ（分解）。高速液体クロマ
トグラフィーで測定した純度は９３．３６％であっｔこ
。the resulting organic solution. Stir at ~J''C for 7 hours, filter the formed crystalline precipitate, wash with fresh N,N-dinotylacetamide, then fresh chetyl ether, and vacuum dry for 2 hours at room temperature (Otsu R27R). -7-[(Z
)-2-(,2-l-'J7 ethylmethylaminothyanoluguyl)-2-(2-L-butoxycarbonylpropinooxyimino)acedo21~]-3-(/
-Pyridinium methyl)-3-cephem-gucarphonic acid ester N,N-dimethylacetamide solvate\
X \ \ \ <y (Yield otsuj2%
) was obtained. 'P, /30°C (decomposition). The purity measured by high performance liquid chromatography was 93.36%.
実施例２ 実施例／の方法を以下のようにして繰り返した。Example 2 The method of Example/ was repeated as follows.
五塩化リン７７３ｇのジクロロメタン／ ２０ ｙｎｌ
冷攪拌溶液（−７，３−′Ｃ）に、（Ｚ）−２−（２−
を−ブトキシカルボニルプロプ−２−オキシイミノ）−
２〜（，２−）リフェニルメチルアミノチアゾルーｊ−
イル）酢酸／７３２９を一度に加えた。773 g of phosphorus pentachloride dichloromethane / 20 ynl
(Z)-2-(2-
-butoxycarbonylprop-2-oximino)-
2-(,2-)liphenylmethylaminothiazole j-
yl)acetic acid/7329 was added in one portion.
これをおよそ−１０〜−／３”Ｃに保持しながら３０分
間攪拌し、トリエチルアミン１０３ｍ１を含有する水ｇ
Ｏｍｌを加えて希釈した。この反応液を３分間攪拌した
のち、有機層を分取し、水層を廃棄した。有機層を、（
乙Ｒ、７Ｒ）−７−ア２ノー３−（／−ピリジニウムメ
チル）−３−セフェム−ｊ−カルホン酸・二塩酸塩／ｌ
／３Ｑをトリエチルアミン／ ７３ ｍｌを含有するＮ
、Ｎ−ジメチルアセトアミド、ｆざｍｌに懸濁した冷攪
拌懸副液（−１０°Ｃ）に、７０分間を要して滴加した
。これをおよそ−５〜０°Ｃで３０分間攪拌して約＋３
′Ｃまで暖め、水２０θｍｌを加えて希釈した。この水
性反応液を２分間攪拌したのち、有機層を分取し。This was stirred for 30 minutes while maintaining the temperature at approximately -10 to -/3"C, and water containing 103 ml of triethylamine was added.
It was diluted by adding Oml. After stirring this reaction solution for 3 minutes, the organic layer was separated and the aqueous layer was discarded. The organic layer (
OtsuR, 7R)-7-a2-no-3-(/-pyridiniummethyl)-3-cephem-j-carphonic acid dihydrochloride/l
/N containing 3Q triethylamine/73 ml
, N-dimethylacetamide, was added dropwise over a period of 70 minutes to a cold stirring suspension solution (-10°C) suspended in 1 ml of f. Stir this for 30 minutes at approximately -5 to 0°C to approximately +3
The mixture was warmed to 'C' and diluted with 20 ml of water. After stirring this aqueous reaction solution for 2 minutes, the organic layer was separated.
水層を廃棄した。有機層を酢酸エチルスθＯｍｉおよび
ジエチルエーテル／θＯｍｉで更に希釈し、およそ２０
〜２３°Ｃで激しく攪拌した。ここにセフタジシムの製
造中間体のＮ、Ｎ−ジメチルアセトアミド溶媒和物の種
結晶を植えて結晶化を起こさせ・２０〜２５°Ｃで３ｇ
分間攪拌したのち、０°Ｃまで冷却し、約２時間攪拌を
継続した。混液を濾過し。The aqueous layer was discarded. The organic layer was further diluted with ethyl acetate θOmi and diethyl ether/θOmi to approximately 20
Stir vigorously at ~23°C. Seed crystals of N,N-dimethylacetamide solvate, a manufacturing intermediate of ceftazime, were planted here to cause crystallization. 3g at 20-25°C.
After stirring for a minute, the mixture was cooled to 0°C and stirring was continued for about 2 hours. Filter the mixture.
濾過ケークをＮ、Ｎ−ジメチルアセトアミド１０ｍ１お
よびジエチルエーテル／θｍ？の混液で洗浄して最後に
ジェチルエーテルグＯｍｌで洗浄し、３３’Ｃで約／乙
時間真空乾燥してセフタジジムの製造中間体のＮ、Ｎ−
ジメチルアセトアミド溶媒和物（Ｎ。The filter cake was mixed with 10 ml of N,N-dimethylacetamide and diethyl ether/θm? Finally, it was washed with Oml of ethyl ether, and vacuum dried at 33'C for about 1 hour to remove the N,N-
Dimethylacetamide solvate (N.
Ｎ−ジメチルアセドアｊ ｌ” ｉ ！ｒモル）を約７
ｇ％の収率で得た。About 7 N-dimethylacedo
It was obtained in a yield of g%.
実施例３
セフタジジム・二塩酸塩
窒素で置換した。２Ａ；Ｏｍｌ容の３首広底フラスコに
約／３°Ｃに冷却したギ酸６２．２ｍ１（７３，９９）
を入れる。これを攪拌して、ここに実施例／またはスで
得たセフタシシムの製造中間体３２θ７（３７９ｍＭ）
を加える。この溶液を３ｇ分間攪拌したのち、２０°Ｃ
引下に保持しながら塩酸７３３ｍ１（／３．１ｇ）を加
えて約３時間攪拌する。生成するトリフェニルメタノー
ルを濾過してギ酸および水で洗浄する。Ｐ液を冷却して
アセトン約ざｊθｍｌに加えたのち、この冷スラリーを
約２時間攪拌する。生成物を枦取しアセトンで洗浄して
標記化合物を約乙コ％の収率で得る。Example 3 Ceftazidime dihydrochloride Nitrogen substitution. 2A; 62.2 ml of formic acid (73,99) cooled to approx. /3°C in an Oml three-necked wide-bottomed flask.
Put in. Stir this to prepare the ceftasisim production intermediate 32θ7 (379mM) obtained in Example/S.
Add. After stirring this solution for 3 g, it was heated to 20°C.
While keeping the mixture under pressure, add 733 ml (/3.1 g) of hydrochloric acid and stir for about 3 hours. The resulting triphenylmethanol is filtered and washed with formic acid and water. After cooling the P solution and adding it to about 50 ml of acetone, this cold slurry is stirred for about 2 hours. The product is taken up and washed with acetone to give the title compound in a yield of about 1%.
ＮＭＲ（ＤＭＳＯ−ｄ ） ：δ／：５（５’ （ｓ
、 ２ＣＨＪ） 、夕３３（ｄ。NMR(DMSO-d) :δ/:5(5'(s
, 2CHJ), evening 33 (d.
Ｊ＝３Ｈｚ、乙−Ｈ）、乙、θ／（ｄｄ、Ｊ＝９．３；
Ｈｚ、７ Ｈ）。J=3Hz, Otsu-H), Otsu, θ/(dd, J=9.3;
Hz, 7H).
７θ０（ｓ、アミノチアゾール）、＆３０．．！７７３
；（ｔ 、、Ｊ＝６Ｈｚ ）、１７３（む、Ｊ−乙Ｈｚ
）、９．２３（ｄ、Ｊ−乙Ｈｚ。7θ0 (s, aminothiazole), &30. ．． ! 773
;(t,, J=6Hz), 173(mu, J-Otsu Hz
), 9.23 (d, J-Otsu Hz.
ピリジニウム・プロトン）、９．７２（ｄ、Ｊ＝９．ア
セトアミド・プロトン）。pyridinium proton), 9.72 (d, J=9.acetamido proton).
特１［］人 イーライ・リリー・アンド・カンパニ
ーし；二、−」１Special 1 [] person Eli Lilly &Company; 2, -” 1
Claims (9)
表わし、Ｘはθ３〜３．０である。］ で表わされる化合物。(1) Formula (1) [In the formula, DMAC represents N,N-dimethylacetamide, and X is θ3 to 3.0. ] A compound represented by:
物。(2) The compound according to claim (1), wherein x is 05.
物。(3) The compound according to claim (1), wherein x is /θ.
合物。(4) The compound according to claim (1), wherein x is /, or.
物。(5) The compound according to claim (1), wherein x is θ.
合物。(6) x is 2. The compound according to claim (1), which is j.
−２−（２−ｔ−フトキシカルホニルブロプーノーオ
キシイミノ）−２−（２−トリフェニルメチルアミノチ
アツルーグーイル）］アセチルハライドを（乙Ｒ，７Ｒ
）−７−アミノ−３−（／−ピリジニウムメチル）−３
−セフェム−グーカルホン酸塩と反応させて式（１） ％式％） ［式中、ＤＭＡＣはＮ、Ｎ−ジメチルアセトアミドを表
わし、Ｘはθ３〜３．０である。］ で表わされる化合物を得ることを特徴とする製造方法。(7) [(Z) in N,N-dimethylacetamide
-2-(2-t-phthoxycarbonylbropinooxyimino)-2-(2-triphenylmethylaminothiatruguyl)]acetyl halide (R, 7R
)-7-amino-3-(/-pyridiniummethyl)-3
-Cephem-gucarphonate to form a compound of formula (1) (% formula %) [wherein, DMAC represents N,N-dimethylacetamide, and X is θ3 to 3.0. ] A manufacturing method characterized by obtaining a compound represented by these.
ことを特徴とするセフタジジムまたはその製薬上許容さ
れる塩の製造方法。 （以下余白） ［式中、ＤＭＡＣはＮ、Ｎ−ジメチルアセトアミドを表
わし、又は０５〜３．θである。］(8) A method for producing ceftazidime or a pharmaceutically acceptable salt thereof, which comprises subjecting a compound represented by formula (1) to a deprotection reaction. (The following is a blank space) [In the formula, DMAC represents N,N-dimethylacetamide, or 05 to 3. θ. ]
により保護基を除去する特許請求の範囲（８）記載の方
法。(9) The method according to claim (8), wherein the protecting group is removed by treating the compound represented by formula (1) with an acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US45344582A | 1982-12-27 | 1982-12-27 | |
| US453445 | 1982-12-27 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5052010A Division JPH069647A (en) | 1982-12-27 | 1993-03-12 | New cephalosporin intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59130889A true JPS59130889A (en) | 1984-07-27 |
| JPH0834744B2 JPH0834744B2 (en) | 1996-03-29 |
Family
ID=23800618
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP25226383A Expired - Lifetime JPH0834744B2 (en) | 1982-12-27 | 1983-12-23 | Novel cephalosporin intermediate |
| JP5052010A Pending JPH069647A (en) | 1982-12-27 | 1993-03-12 | New cephalosporin intermediate |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5052010A Pending JPH069647A (en) | 1982-12-27 | 1993-03-12 | New cephalosporin intermediate |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4525587A (en) |
| EP (1) | EP0113568B1 (en) |
| JP (2) | JPH0834744B2 (en) |
| KR (1) | KR870000612B1 (en) |
| CA (1) | CA1245629A (en) |
| DE (1) | DE3381408D1 (en) |
| DK (1) | DK164061C (en) |
| GB (1) | GB2132616B (en) |
| GR (1) | GR79485B (en) |
| HK (1) | HK17089A (en) |
| HU (1) | HU191911B (en) |
| IE (1) | IE56485B1 (en) |
| IL (1) | IL70470A (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4694079A (en) * | 1985-07-29 | 1987-09-15 | Bristol-Myers Company | 3-propenyl cephalosporin solvates |
| AT387022B (en) * | 1986-06-04 | 1988-11-25 | Biochemie Gmbh | METHOD FOR PRODUCING A NEW CRYSTALLINE SHAPE OF A CEFALOSPORINE DERIVATIVE |
| US4734408A (en) * | 1986-12-17 | 1988-03-29 | Eli Lilly And Company | Crystalline cephalosporin antibiotic salts and solvates |
| AT388736B (en) * | 1987-10-08 | 1989-08-25 | Biochemie Gmbh | Novel stable crystalline forms of ceftazidime t-butyl ester and process for their preparation |
| GB8802622D0 (en) * | 1988-02-05 | 1988-03-02 | Glaxo Group Ltd | Chemical compound |
| US5831085A (en) * | 1997-01-16 | 1998-11-03 | Lupin Laboratories Limited | Process for manufacture of cephalosporin such as ceftazidime and intermediate thereof |
| CN106317081B (en) * | 2016-08-22 | 2018-08-31 | 山东罗欣药业集团恒欣药业有限公司 | A kind of anti-infectives cefotaxime crystalline compounds and its pharmaceutical composition |
| CN106397458A (en) * | 2016-09-23 | 2017-02-15 | 临沂草之美医药科技有限公司 | Ceftazidime crystal compound as drug for treating infection during surgical operation |
| CN106432280A (en) * | 2016-09-23 | 2017-02-22 | 临沂草之美医药科技有限公司 | Medicine ceftazidime crystalline compound for treating surgical operation infection |
| CN107722040A (en) * | 2017-10-10 | 2018-02-23 | 南京志坤环保科技有限公司 | A kind of membrane separating method and device for recycling ceftazidime mother liquor |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5448784A (en) * | 1977-09-27 | 1979-04-17 | Toyama Chem Co Ltd | N,n-dimethylacetamide adduct of cephalosporin and its preparation |
| JPS54154786A (en) * | 1978-05-26 | 1979-12-06 | Glaxo Group Ltd | Cephalosporin compound |
| JPS5612397A (en) * | 1979-05-25 | 1981-02-06 | Glaxo Group Ltd | Intermediate for manufacture of cephalosporin antibiotic |
| JPS58194871A (en) * | 1982-04-29 | 1983-11-12 | グラクソ・グル−プ・リミテツド | Improvement on manufacture of antibiotic |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR228726A1 (en) * | 1978-05-26 | 1983-04-15 | Glaxo Group Ltd | PROCEDURE FOR THE PREPARATION OF ANTIBIOTIC (6R, 7R) -7 - ((Z) -2- (2-AMINOTIAZOL-4-IL) -2- (2-CARBOXIPROP-2-OXIIMINO) ACETAMIDO) -3- (1- PIRIDINIOMETIL) CEF-3-EM-4-CARBOXILATO |
-
1983
- 1983-12-16 EP EP19830307675 patent/EP0113568B1/en not_active Expired - Lifetime
- 1983-12-16 DE DE8383307675T patent/DE3381408D1/en not_active Expired - Lifetime
- 1983-12-16 GB GB8333667A patent/GB2132616B/en not_active Expired
- 1983-12-18 IL IL7047083A patent/IL70470A/en not_active IP Right Cessation
- 1983-12-19 CA CA000443622A patent/CA1245629A/en not_active Expired
- 1983-12-19 DK DK584183A patent/DK164061C/en not_active IP Right Cessation
- 1983-12-20 GR GR73287A patent/GR79485B/el unknown
- 1983-12-21 KR KR1019830006051A patent/KR870000612B1/en not_active IP Right Cessation
- 1983-12-22 IE IE3037/83A patent/IE56485B1/en not_active IP Right Cessation
- 1983-12-23 HU HU834468A patent/HU191911B/en not_active IP Right Cessation
- 1983-12-23 JP JP25226383A patent/JPH0834744B2/en not_active Expired - Lifetime
-
1984
- 1984-02-03 US US06/576,609 patent/US4525587A/en not_active Expired - Lifetime
-
1989
- 1989-02-23 HK HK17089A patent/HK17089A/en not_active IP Right Cessation
-
1993
- 1993-03-12 JP JP5052010A patent/JPH069647A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5448784A (en) * | 1977-09-27 | 1979-04-17 | Toyama Chem Co Ltd | N,n-dimethylacetamide adduct of cephalosporin and its preparation |
| JPS54154786A (en) * | 1978-05-26 | 1979-12-06 | Glaxo Group Ltd | Cephalosporin compound |
| JPS5612397A (en) * | 1979-05-25 | 1981-02-06 | Glaxo Group Ltd | Intermediate for manufacture of cephalosporin antibiotic |
| JPS58194871A (en) * | 1982-04-29 | 1983-11-12 | グラクソ・グル−プ・リミテツド | Improvement on manufacture of antibiotic |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2132616B (en) | 1986-08-06 |
| EP0113568B1 (en) | 1990-04-04 |
| KR870000612B1 (en) | 1987-03-25 |
| JPH0834744B2 (en) | 1996-03-29 |
| IL70470A (en) | 1988-04-29 |
| GR79485B (en) | 1984-10-30 |
| DK164061C (en) | 1992-09-28 |
| IL70470A0 (en) | 1984-03-30 |
| IE833037L (en) | 1984-06-27 |
| HU191911B (en) | 1987-04-28 |
| GB2132616A (en) | 1984-07-11 |
| KR840007013A (en) | 1984-12-04 |
| GB8333667D0 (en) | 1984-01-25 |
| DK584183D0 (en) | 1983-12-19 |
| DK584183A (en) | 1984-06-28 |
| DE3381408D1 (en) | 1990-05-10 |
| JPH069647A (en) | 1994-01-18 |
| EP0113568A2 (en) | 1984-07-18 |
| US4525587A (en) | 1985-06-25 |
| EP0113568A3 (en) | 1985-07-31 |
| CA1245629A (en) | 1988-11-29 |
| DK164061B (en) | 1992-05-04 |
| IE56485B1 (en) | 1991-08-14 |
| HK17089A (en) | 1989-03-03 |
| HUT34209A (en) | 1985-02-28 |
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